Chang L J, He J
Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center and McKnight Brain Institute, University of Florida, Gainesville 32610-0266, USA.
Curr Opin Mol Ther. 2001 Oct;3(5):468-75.
Both AIDS and cancer are linked to immune dysfunctions of the body which are characterized by the persistence of disease-afflicted cells. To effect a cure with novel gene therapy approaches, these diseased cells must be eliminated either directly or indirectly using cytotoxic or suicide genes, or via activation of specific immune functional cells. Retroviral vectors are useful tools for long-term genome modification owing to their ability to integrate into host chromosomes. However, most oncoretroviruses, including murine leukemia virus (MLV), require cell division to facilitate nuclear entry; this has restricted the application of murine oncoretroviral vectors to cell targets that are actively dividing. Accordingly, gene transfer into hematopoietic stem cells (HSCs) and terminally differentiated cells such as muscles, neurons and dendritic cells (DCs) has been limited with the conventional oncoretroviral vectors. The lentiviral family of retroviruses, including human immunodeficiency virus type 1 (HIV-1), has been developed into useful gene transfer tools. Lentiviral vectors carry several nuclear entry viral proteins, and therefore can target slowly-dividing and non-dividing cells. To activate immune response against cancer or HIV infection, long-term marking of the target cells is not necessary. However, to establish intracellular defense to prevent HIV infection, prolonged genetic modification of target cells such as HSCs will be required. Due to the poor transduction efficiency and the problem of transgene silencing over time with oncoretroviral vectors, most gene therapy studies for AIDS and cancer using oncoretroviral vectors remain proof-of-concept studies. Here we will discuss recent developments in the use of retroviral vectors, including HIV-1-derived lentiviral vectors, for the treatment of AIDS and cancer, and their future therapeutic potential.
艾滋病和癌症都与身体的免疫功能障碍有关，其特征是患病细胞持续存在。为了用新型基因治疗方法实现治愈，必须使用细胞毒性或自杀基因直接或间接消除这些患病细胞，或者通过激活特定的免疫功能细胞来消除。逆转录病毒载体因其能够整合到宿主染色体中，是进行长期基因组修饰的有用工具。然而，大多数致癌逆转录病毒，包括鼠白血病病毒（MLV），需要细胞分裂以促进核进入；这限制了鼠致癌逆转录病毒载体在活跃分裂的细胞靶标中的应用。因此，使用传统的致癌逆转录病毒载体将基因转移到造血干细胞（HSC）以及终末分化细胞如肌肉、神经元和树突状细胞（DC）中受到了限制。逆转录病毒的慢病毒家族，包括1型人类免疫缺陷病毒（HIV-1），已被开发成为有用的基因转移工具。慢病毒载体携带几种核进入病毒蛋白，因此可以靶向缓慢分裂和不分裂的细胞。为了激活针对癌症或HIV感染的免疫反应，对靶细胞进行长期标记并非必要。然而，为了建立细胞内防御以预防HIV感染，将需要对诸如HSC等靶细胞进行长期的基因修饰。由于致癌逆转录病毒载体的转导效率低以及随着时间推移转基因沉默的问题，大多数使用致癌逆转录病毒载体治疗艾滋病和癌症的基因治疗研究仍处于概念验证研究阶段。在这里，我们将讨论使用逆转录病毒载体，包括源自HIV-1的慢病毒载体，治疗艾滋病和癌症的最新进展及其未来的治疗潜力。
